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Article
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Compensatory growth and recovery of cartilage cytoarchitecture after transient cell death in fetal mouse limbs
How growing organs recover from transient injuries is unclear. Here, authors used mouse models of transient cell death in the limb cartilage to identify cellular and molecular mechanisms (e.g. mTORC1) involved in cartilage repair and catch-up growth.
- Chee Ho H’ng
- , Shanika L. Amarasinghe
- & Alberto Rosello-Diez
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| Open Access
SOXC are critical regulators of adult bone mass
Angelozzi et al. uncover key mechanisms involved in physiological and pathological bone mass remodeling by showing that SOXC transcription factors regulate the bone formation and resorption balance via critical roles in LepR+ mesenchymal stem cells.
- Marco Angelozzi
- , Anirudha Karvande
- & Véronique Lefebvre
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Specific heterozygous variants in MGP lead to endoplasmic reticulum stress and cause spondyloepiphyseal dysplasia
Biallelic loss-of-function variants in the gene encoding Matrix Gla Protein (MGP) are known to cause a recessive disorder called Keutel syndrome. Here, the authors report that heterozygous missense variants affecting one particular cysteine residue of MGP can cause a clinically distinct, dominant disorder, likely via impaired signal peptide processing leading to cellular stress and apoptosis.
- Ophélie Gourgas
- , Gabrielle Lemire
- & Monzur Murshed
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| Open Access
Multimodal spatiotemporal transcriptomic resolution of embryonic palate osteogenesis
Multimodal spatiotemporal transcriptomic resolution of palatal osteogenesis identifies previously unreported enriched genes in developing palate, paving the way toward viable diagnostic and therapeutic targets for cleft palate disorders.
- Jeremie Oliver Piña
- , Resmi Raju
- & Rena N. D’Souza
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The NAD salvage pathway in mesenchymal cells is indispensable for skeletal development in mice
Deficiency in NAD+ has been implicated in skeletal deformities during development in both humans and mice. Here, the authors use mice that lack the critical enzyme of the NAD+ salvage pathway Nampt in mesenchymal lineage cells to show that the NAD salvage pathway is indispensable for endochondral but not intramembranous bone development.
- Aaron Warren
- , Ryan M. Porter
- & Maria Almeida
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Bone marrow endosteal stem cells dictate active osteogenesis and aggressive tumorigenesis
This study identified a new class of skeletal stem cells in the endosteal space of bone marrow, which are abundant in young bone marrow, express Fgfr3 with osteoblast-chondrocyte transitional identities and can turn into bone tumor-making cells.
- Yuki Matsushita
- , Jialin Liu
- & Noriaki Ono
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BRD9-mediated chromatin remodeling suppresses osteoclastogenesis through negative feedback mechanism
Osteoclast differentiation is critical for bone homeostasis. The authors show the negative feedback regulation of BRD9-mediated chromatin remodeling on osteoclastogenesis via interferon beta signaling and its therapeutic potential for bone diseases.
- Jiahui Du
- , Yili Liu
- & Xinquan Jiang
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| Open Access
The fate of early perichondrial cells in developing bones
In endochondral bone development, bone-forming osteoblasts and bone marrow stromal cells have dual origins in the fetal cartilage and its surrounding perichondrium. Here they show that perichondrial cells are destined to become adipocyte-biased stromal cells, indicating that marrow stromal compartments are defined by their cells of origin.
- Yuki Matsushita
- , Angel Ka Yan Chu
- & Noriaki Ono
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Altered developmental programs and oriented cell divisions lead to bulky bones during salamander limb regeneration
Normal limb development relies on synchronized formation of cartilage and bone. Here, the authors show that in salamander limb regeneration these processes are decoupled: ossification occurs after the final size of regenerating cartilage is reached, allowing fast regeneration and leading to bulky bones.
- Marketa Kaucka
- , Alberto Joven Araus
- & Igor Adameyko
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Impaired mitochondrial oxidative metabolism in skeletal progenitor cells leads to musculoskeletal disintegration
Skeletal progenitors provide a reservoir for bone-forming osteoblasts. However, the major energy source for their osteogenesis remains unresolved. Here, the authors demonstrate that ESCIT-mediated regulation of mitochondrial metabolism is required for osteogenesis.
- Chujiao Lin
- , Qiyuan Yang
- & Jae-Hyuck Shim
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Suppression of heterotopic ossification in fibrodysplasia ossificans progressiva using AAV gene delivery
Fibrodysplasia ossificans progressiva is an ultra-rare genetic disorder with progressive heterotopic ossification. Yang et al develop different gene therapy approaches and show their efficacy in mouse models and in human induced pluripotent stem cells.
- Yeon-Suk Yang
- , Jung-Min Kim
- & Jae-Hyuck Shim
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Article
| Open Access
WRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome
Short stature is a hallmark of Werner Syndrome, but the underlying mechanisms are not well studied. Here they report that WRN regulates bone development and growth by opening SHOX-G-quadruplexes via its helicase activity both in vitro and in vivo.
- Yuyao Tian
- , Wuming Wang
- & Wai-Yee Chan
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Article
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GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway
Lysosomal biogenesis errors often result in diseases including mucolipidosis. Here Zhang and Yang et al. identify TMEM251/GCAF as a mannose-6-phosphate modification regulator that is necessary for correct lysosomal targeting, and classify Mucolipidosis Type V as resulting from GCAF mutations.
- Weichao Zhang
- , Xi Yang
- & Ming Li
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| Open Access
TET enzymes regulate skeletal development through increasing chromatin accessibility of RUNX2 target genes
Here the authors investigate the role of the TET family of DNA demethylases in mammalian skeletal development. They find that loss of TETs leads to hypermethylation that results in decreased chromatin accessibility of RUNX2 target genes, repressing osteoblast differentiation and leading to skeletal defects in mouse such as short limbs.
- Lijun Wang
- , Xiuling You
- & Weiguo Zou
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Periosteal stem cells control growth plate stem cells during postnatal skeletal growth
Intramembranous and endochondral bone formation have been considered to be independent processes mediated by independent stem cells. Here the authors show that periosteal stem cells participate in both types of bone formation, supporting endochondral formation by producing Ihh.
- Masayuki Tsukasaki
- , Noriko Komatsu
- & Hiroshi Takayanagi
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Mechanical forces couple bone matrix mineralization with inhibition of angiogenesis to limit adolescent bone growth
The study shows that mechanical forces trigger secretion of the extracellular matrix protein dentin matrix protein 1 from osteoblasts. This transforms bone growth-promoting blood vessels into a quiescent subtype to limit bone growth at the end of adolescence.
- Maria Dzamukova
- , Tobias M. Brunner
- & Max Löhning
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A neomorphic variant in SP7 alters sequence specificity and causes a high-turnover bone disorder
SP7 is a transcription factor required for osteoblast differentiation and bone formation. A neomorphic mutation in SP7 was found to alter DNA binding specificity, causing a complex skeletal disorder in both mice and humans.
- Julian C. Lui
- , Adalbert Raimann
- & Jeffrey Baron
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| Open Access
Mesenchymal stromal cell-derived septoclasts resorb cartilage during developmental ossification and fracture healing
Developmental and regenerative bone formation require the removal of chondrocytes and matrix. Here the authors show that these processes involve mesenchymal stromal cell-derived septoclasts, which disappear after the completion of development but re-emerge during fracture healing.
- Kishor K. Sivaraj
- , Paul-Georg Majev
- & Ralf H. Adams
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| Open Access
Type-I collagen produced by distinct fibroblast lineages reveals specific function during embryogenesis and Osteogenesis Imperfecta
Collagen is the most abundant protein in the human body. Here, the authors show that different classes of fibroblasts produce collagen of unique functions with different impacts on embryo development and bone formation.
- Yang Chen
- , Sujuan Yang
- & Raghu Kalluri
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Single-cell analysis identifies a key role for Hhip in murine coronal suture development
Craniofacial development depends on formation and maintenance of sutures between bones of the skull. Here the authors identify enriched expression of the hedgehog inhibitor Hhip, specifically in the mesenchyme of the murine coronal suture, and show sutural dysgenesis in Hhip−/− mutants.
- Greg Holmes
- , Ana S. Gonzalez-Reiche
- & Ethylin Wang Jabs
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STAT3 is critical for skeletal development and bone homeostasis by regulating osteogenesis
Autosomal dominant hyper-immunoglobulin E syndrome (AD-HIES) is associated with mutations in STAT3, and clinical manifestations include skeletal deformities. Here, the authors show that inactivation of STAT3 in osteoblast induces AD-HIES-like skeletal defects by impairing osteogenesis, and show that pharmacological STAT3 activation rescues the phenotype.
- Siru Zhou
- , Qinggang Dai
- & Lingyong Jiang
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| Open Access
Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin
The molecular circuitry that drives dendrite formation during osteocytogenesis remains poorly understood. Here the authors show that deletion of Sp7, a gene linked to rare and common skeletal disease, in mature osteoblasts and osteocytes causes severe defects in osteocyte dendrites.
- Jialiang S. Wang
- , Tushar Kamath
- & Marc N. Wein
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Application of 3D MAPs pipeline identifies the morphological sequence chondrocytes undergo and the regulatory role of GDF5 in this process
Inability to image large numbers of growth plate chondrocytes while retaining their spatial context during analysis has hindered the study of bone development. Here, the authors present a pipeline called 3D MAPs and use it to uncover morphogenic behaviors and growth strategies in normal bones as well as aberrations in Gdf5 KO bones.
- Sarah Rubin
- , Ankit Agrawal
- & Elazar Zelzer
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| Open Access
Mesomelic dysplasias associated with the HOXD locus are caused by regulatory reallocations
Mesomelic dysplasia, a severe shortening and bending of the limb, has been linked to rearrangements in the HoxD cluster in humans and mice. Here the authors engineer a 1 Mb inversion including the HoxD gene cluster and use this model to provide a mechanistic framework to understand and unify the molecular origins of human mesomelic dysplasia associated with 2q31.
- Christopher Chase Bolt
- , Lucille Lopez-Delisle
- & Denis Duboule
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| Open Access
The developing mouse coronal suture at single-cell resolution
The development of the coronal suture remains incompletely understood. Here the authors perform scRNA-seq and expression validation to uncover the cellular diversity within the murine embryonic coronal suture, thus revealing possible mechanisms for its loss in craniosynostosis.
- D’Juan T. Farmer
- , Hana Mlcochova
- & Stephen R. F. Twigg
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Article
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Skeletal stem and progenitor cells maintain cranial suture patency and prevent craniosynostosis
Cranial sutures are major growth centers for the skull vault and premature fusion leads to pathological fusion, craniosynostosis. Here the authors isolate Wnt responsive skeletal stem and progenitor cells from sutures, that can be transplanted together with Wnt3a protein to repair craniosynostosis in a mouse model.
- Siddharth Menon
- , Ankit Salhotra
- & Natalina Quarto
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| Open Access
SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts
Hedgehog signaling is essential for bone formation. Here, the authors show that the transmembrane protein SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts, suggesting it may be a potential therapeutic target to enhance bone formation.
- Jun Sun
- , Dong Yeon Shin
- & Matthew B. Greenblatt
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Article
| Open Access
A RUNX2 stabilization pathway mediates physiologic and pathologic bone formation
Runx2 is essential for tuning the generation of bone from skeletal stem cells (SSCs). Here, the authors demonstrate that the CK2/HAUSP pathway stabilizes RUNX2 protein thereby regulating the commitment of SSCs to osteoprogenitors as well as their subsequent maturation, and that inhibition of this pathway can block heterotopic ossification.
- Jung-Min Kim
- , Yeon-Suk Yang
- & Jae-Hyuck Shim
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Dstyk mutation leads to congenital scoliosis-like vertebral malformations in zebrafish via dysregulated mTORC1/TFEB pathway
Congenital scoliosis is a complex genetic disorder characterized by vertebral malformation. Here, the authors demonstrate that loss of dstyk leads to scoliosis in zebrafish due to dysregulated biogenesis of notochord vacuoles and that DSTYK is required for lysosome biogenesis through mTORC1 regulation.
- Xianding Sun
- , Yang Zhou
- & Lin Chen
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| Open Access
A Wnt-mediated transformation of the bone marrow stromal cell identity orchestrates skeletal regeneration
Bone marrow stromal cells (BMSCs) lining sinusoidal blood vessels are mesenchymal cells whose function is critical for the skeleton. Here the authors show that quiescent CXCL12-expressing BMSCs can convert into a skeletal stem cell-like state, and differentiate into cortical bone osteoblasts only in response to injury.
- Yuki Matsushita
- , Mizuki Nagata
- & Noriaki Ono
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| Open Access
Increased autophagy in EphrinB2-deficient osteocytes is associated with elevated secondary mineralization and brittle bone
Osteoblasts mediate bone formation, and their differentiation requires expression of EphrinB2. Here, the authors show that EphrinB2 is also expressed by osteocytes, and that its genetic ablation in mice is associated with altered autophagy, elevated mineralization and brittle bone.
- Christina Vrahnas
- , Martha Blank
- & Natalie A. Sims
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| Open Access
Hox11 expressing regional skeletal stem cells are progenitors for osteoblasts, chondrocytes and adipocytes throughout life
Prior evidence suggested mesenchymal stromal cells (MSCs) required for skeletal formation, maintenance, and repair arise postnatally. Here, the authors show that Hoxa11 lineage-marked cells give rise to all skeletal lineages from embryogenesis through adulthood and are upstream progenitors of LepR- and Osx-lineage MSCs
- Kyriel M. Pineault
- , Jane Y. Song
- & Deneen M. Wellik
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| Open Access
Clonal dynamics in osteosarcoma defined by RGB marking
Osteosarcoma is a heterogeneous bone tumour with a high mutational rate. Here the authors use an RGB-based single-cell tracking system to track clonal dynamics in a mouse model of osteosarcoma, which their findings indicate follows a neutral evolution model in which different clones simultaneously coexist and propagate.
- Stefano Gambera
- , Ander Abarrategi
- & Javier García-Castro
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| Open Access
SLC10A7 mutations cause a skeletal dysplasia with amelogenesis imperfecta mediated by GAG biosynthesis defects
The majority of skeletal dysplasia are caused by pathogenic variants in genes required for glycosaminoglycan (GAG) metabolism. Here, Dubail et al. identify genetic variants in the solute carrier family protein SLC10A7 in families with skeletal dysplasia and amelogenesis imperfecta that disrupt GAG synthesis.
- Johanne Dubail
- , Céline Huber
- & Valérie Cormier-Daire
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| Open Access
Tet1 and Tet2 maintain mesenchymal stem cell homeostasis via demethylation of the P2rX7 promoter
Tet-mediated DNA oxidation converts 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), which is essential to regulate different biological processes. Here the authors show that Tet1 and Tet2 regulate mesenchymal stem cell and bone homeostasis through demethylation of P2rX7 promoter.
- Ruili Yang
- , Tingting Yu
- & Songtao Shi
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| Open Access
Desumoylase SENP6 maintains osteochondroprogenitor homeostasis by suppressing the p53 pathway
Osteochondroprogenitors are essential cells for skeletal development and homeostasis. Here the authors show that the desumoylase SENP6 suppresses p53 activity by desumoylating and stabilising TRIM28, and that SENP6 ablation leads to skeletal abnormalities, senescence in osteochondroprogenitors and chondrocytes, and premature ageing.
- Jianshuang Li
- , Di Lu
- & Tao Yang
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| Open Access
Gli1 identifies osteogenic progenitors for bone formation and fracture repair
Skeletal progenitors in postnatal mice are highly heterogeneous. Using lineage tracing and RNA-seq the authors show that Gli1+ cells give rise to all osteoblasts in mice, including those required for healing of bone fractures.
- Yu Shi
- , Guangxu He
- & Fanxin Long
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| Open Access
Bone corticalization requires local SOCS3 activity and is promoted by androgen action via interleukin-6
The strength of long bones is determined by coalescence of trabeculae during corticalization. Here the authors show that this process is regulated by SOCS3 via a mechanism dependent on IL-6 and expression of sex hormones.
- Dae-Chul Cho
- , Holly J. Brennan
- & Natalie A. Sims
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Article
| Open Access
MicroRNA miR-23a cluster promotes osteocyte differentiation by regulating TGF-β signalling in osteoblasts
Control of osteocyte differentiation is not well understood. Here the authors show that the miR-23 cluster represses the TGF-β signalling repressor Prdm16 in osteoblasts, thus enhancing osteocyte differentiation and a low bone mass phenotype.
- Huan-Chang Zeng
- , Yangjin Bae
- & Brendan H. Lee
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Article
| Open Access
SMURF2 regulates bone homeostasis by disrupting SMAD3 interaction with vitamin D receptor in osteoblasts
The balance between osteoclast and osteoblast-mediated bone turnover is essential for bone health and homeostasis. Here the authors show that both germline and osteoblast-specificSmurf2-deficient mice have osteoporosis as a result of increased osteoblast RANKL production and excess osteoclastogenesis.
- Zhan Xu
- , Matthew B. Greenblatt
- & Weiguo Zou
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Article
| Open Access
Blood flow controls bone vascular function and osteogenesis
Formation of new blood vessels and bone is coupled. Here the authors show that blood flow represents a key regulator of angiogenesis and endothelial Notch signalling in the bone, and that reactivation of Notch signalling in the endothelium of aged mice rejuvenates the bone.
- Saravana K. Ramasamy
- , Anjali P. Kusumbe
- & Ralf H. Adams
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Article
| Open Access
EZH1 and EZH2 promote skeletal growth by repressing inhibitors of chondrocyte proliferation and hypertrophy
EZH1 and EZH2 are associated with epigenetic bone and cartilage developmental defects. Here the authors show that cartilage-specific double knockout mice have reduced skeletal growth and how these histone methyltransferases regulate chondrogenesis and endochondral bone development.
- Julian C. Lui
- , Presley Garrison
- & Jeffrey Baron
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Article
| Open Access
Vital staining for cell death identifies Atg9a-dependent necrosis in developmental bone formation in mouse
Apoptosis occurs in numerous developmental processes but a role for necrosis in development is unclear. Here, the authors develop a detecting system of necrosis in the developing mouse and find a form of necrosis that is dependent on the autophagy-related gene Atg9a.
- Yusuke Imagawa
- , Tatsuya Saitoh
- & Yoshihide Tsujimoto
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Article
| Open Access
An interdigit signalling centre instructs coordinate phalanx-joint formation governed by 5′Hoxd–Gli3 antagonism
The molecular mechanisms governing digit joint specification are poorly understood. Here, the authors identify the 5′Hoxd–Gli3 balance as a key regulator of the net interdigital Bmp signalling level in mouse, which in turn regulates phalanx and joint formation.
- Bau-Lin Huang
- , Anna Trofka
- & Susan Mackem
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Article
| Open Access
Polycomb repressive complex 2 regulates skeletal growth by suppressing Wnt and TGF-β signalling
Eed is a polycomb repressive complex 2 component involved in stem cell lineage determination, but little is known about its role in lineage committed cells. Here the authors show that chondrocyte-specific Eed KO mice have skeletal growth defects related to induction of Wnt and TGF-β signalling.
- Fatemeh Mirzamohammadi
- , Garyfallia Papaioannou
- & Tatsuya Kobayashi
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| Open Access
mTORC1 regulates PTHrP to coordinate chondrocyte growth, proliferation and differentiation
mTORC1 is crucial for chondrocyte proliferation and bone growth, but the downstream signalling is not clear. Here, the authors use rapamycin and chondrocyte-specific Tsc1 knockout mice to show that S6K1 can cause nuclear accumulation of Gli2, thus driving PTHrP expression and preventing terminal differentiation of prehypertrophic chondrocytes.
- Bo Yan
- , Zhongmin Zhang
- & Xiaochun Bai
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Article
| Open Access
Mediator MED23 cooperates with RUNX2 to drive osteoblast differentiation and bone development
The transcription factor Runx2 regulates osteoblast differentiation of mesenchymal stem cells. In this manuscript, the authors, using a specific conditional knock-out mouse model and molecular studies, demonstrate that the mediator subunit MED23 binds to Runx2 and is essential for driving mesenchymal stem cells toward an osteoblast fate.
- Zhen Liu
- , Xiao Yao
- & Gang Wang
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Article
| Open Access
IL-17-producing γδ T cells enhance bone regeneration
γδ T cells are innate-like lymphocytes that regulate immune responses by producing IL-17A or IFN-γ, but have no known role in bone healing. Here the authors show a nonimmune bone-regenerative function of IL-17A produced by the Vγ6+ subset in mice.
- Takehito Ono
- , Kazuo Okamoto
- & Hiroshi Takayanagi
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Article
| Open Access
Osteoclast-derived exosomal miR-214-3p inhibits osteoblastic bone formation
In previous studies the authors discovered that miR-214 inhibits osteoblastic bone formation. Here they extend on these findings, using ovariectomized mice and samples from patients with bone fractures, to show that miR-214 is a mediator of osteoclast-osteoblast crosstalk.
- Defang Li
- , Jin Liu
- & Ge Zhang
Systematic HOIP interactome profiling reveals critical roles of linear ubiquitination in tissue homeostasis